Butyric acid derivatives

ABSTRACT

The present invention relates to a compound of the formula I: (Formula I) in which: A, B, R 1 , Z, n and R 2  are as defined in claim  1 . These compounds are useful in the treatment of dyslipidaemia, atherosclerosis and diabetes.

The present invention relates to 4-(arylthio)- or(4-heteroarylthio)butyric acid derivatives that may be used in thetreatment of dyslipidaemia, atherosclerosis and diabetes, topharmaceutical compositions comprising them and to processes forpreparing these compounds.

The invention also relates to the use of these compounds for theproduction of medicaments intended for treating dyslipidaemia,atherosclerosis and diabetes.

In most countries, cardiovascular disease remains one of the majordiseases and the main cause of death. About one third of men develop amajor cardiovascular disease before the age of 60, with women showing alower risk (ratio of 1 to 10). With advancing years (after the age of65, women become just as vulnerable to cardiovascular diseases as men),this disease increases even more in scale. Vascular diseases, such ascoronary disease, strokes, restenosis and peripheral vascular disease,remain the prime cause of death and handicap throughout the world.

Whereas diet and lifestyle can accelerate the development ofcardiovascular diseases, a genetic predisposition leading todyslipidaemia is a significant factor in cardiovascular accidents anddeath.

The development of atherosclerosis appears to be linked mainly todyslipidaemia, which means abnormal levels of lipoproteins in the bloodplasma. This dysfunction is particularly evident in coronary disease,diabetes and obesity.

The concept intended to explain the development of atherosclerosis wasmainly focused on the metabolism of cholesterol and on the metabolism oftriglycerides.

However, since the studies of Randle et al. (Lancet, 1963, 785-789), anovel concept has been proposed: a glucose-fatty acid cycle or Randlecycle, which describes the regulation of the equilibrium between themetabolism of lipids in terms of triglycerides and cholesterol, and theoxygenation of glucose. According to this concept, the inventors havedeveloped a novel programme, the aim of which is to find novel compoundsacting simultaneously on lipid metabolism and glucose metabolism.

Fibrates are well-known therapeutic agents with a mechanism of actionvia the “Peroxisome Proliferator Activated Receptors”. These receptorsare the main regulators of lipid metabolism in the liver (PPARαisoform). In the last 10 years, thiazolidinediones have been describedas powerful hypoglycaemiant agents in man and animals. It has beenreported that thiazolidinediones are powerful selective activators ofanother isoform of PPARs: PPARγ (Lehmann et al., J. Biol. Chem., 1995,270, 12953-12956).

The inventors have discovered a novel class of compounds that arepowerful activators of the PPARα and PPARγ isoforms. On account of thisactivity, these compounds have a considerable hypolipidaemiant andhypoglycaemiant effect.

The compounds of the invention correspond to formula (I) below:

in which:

A represents carboxyl; (C₆-C₁₈)aryloxycarbonyl in which the aryl groupis optionally substituted; (C₁-C₁₄)alkoxycarbonyl in which the alkylgroup is optionally substituted; —CO—NHOH; -tetrazolyl;

B represents an optionally substituted ethylene group —CH₂—CH₂—;

R¹ represents a hydrogen atom; optionally substituted (C₁-C₁₄)alkyl;optionally substituted (C₆-C₁₈)aryl; optionally substituted heteroaryl;(C₆-C₁₈)aryl(C₁-C₁₄)alkyl in which each of the aryl and/or alkylradicals are optionally substituted; and heteroaryl(C₁-C₁₄)alkyl inwhich each of the heteroaryl and/or alkyl radicals are optionallysubstituted;

Z represents S or Se;

n is an integer equal to 0, 1 or 2;

R² represents optionally substituted (C₆-C₁₈)aryl; optionallysubstituted heteroaryl; or optionally substituted heterocycle containingan aromatic moiety; and when R¹ represents optionally substituted(C₆-C₁₈)aryl, then R² can also represent (C₁-C₁₄)alkyl;

it being understood that when R¹ represents naphthyl or 4-methoxyphenyl,A represents carboxyl or methoxycarbonyl, B represents ethylene, nrepresents 0, and Z represents S or Se, then R² does not representphenyl, the stereoisomers thereof and the addition salts thereof withacids or bases.

In the context of the invention, the term “alkyl” means a linear orbranched hydrocarbon-based chain containing from 1 to 14 carbon atoms,preferably from 1 to 10 and better still from 1 to 6 carbon atoms, forexample from 1 to 4 carbon atoms.

Examples of alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl,iso-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl,1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl,3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl,4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylhexyl,5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and7,7-dimethyloctyl-octyl radicals.

The term “aryl group” means a monocyclic or polycyclic carbocyclicaromatic group containing from 6 to 18 carbon atoms.

Aryl groups that may be mentioned include phenyl, naphthyl, anthryl andphenanthryl.

The heteroaryl groups are monocyclic or polycyclic heterocyclic aromaticgroups comprising hetero atoms generally chosen from O, S and N,optionally in oxidised form (in the case of S and N).

Preferably, at least one of the monocydes constituting the heterocyclecomprises from 1 to 4 endocyclic hetero atoms and better still from 1 to3 hetero atoms.

Preferably, the heterocycle consists of one or more monocycles eachbeing 5- to 7-membered.

Examples of 5- to 7-membered monocyclic heteroaryls are especiallypyridine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole,isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine,thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.

Examples of bicyclic heteroaryls in which each monocycle is 5- to7-membered are chosen from indolizine, indole, isoindole, benzofuran,benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane,benzothiofurazane, purine, quinoline, isoquinoline, cinnoline,phthalazine, quinazoline, quinoxaline, naphthyridines, pyrazolotriazine(such as pyrazolo-1,3,4-triazine), pyrazolepyrimidine and pteridine.

Preferred heteroaryls that may be mentioned include quinolyl, pyridyl,benzothiazolyl and triazolyl.

The tricyclic heteroaryls in which each monocycle is 5- to 7-memberedare chosen, for example, from acridine, phenazine and carbazole.

According to the invention, the expression “heterocycle containing anaromatic moiety” means a heterocycle consisting of one or more monocydeseach preferably being 5- to 7-membered, in which at least one of themonocycles is aromatic, and at least one of the monocydes isheterocyclic and in which the monocycles are ortho- or peri-fused inpairs. It should be understood that the non-aromatic monocycles may besaturated or unsaturated and that the aromatic monocycle is heterocyclicor non-heterocyclic. The heterocyclic monocycle(s) contain(s) one ormore endocyclic hetero atoms (preferably 1 to 4 and better still 1 to 3)chosen from O, N and S, optionally in oxidised form (in the case of S orN).

The carbocyclic aromatic monocydes of the heterocycle containing anaromatic moiety are preferably phenyl nuclei.

The heterocyclic aromatic monocycles of the heterocycle containing anaryl moiety are preferably pyridine, furan, thiophene, pyrrole,pyrazole, imidazole, thiazole, isoxazole, isothiazole, furazane,pyridazine, pyrimidine, pyrazine, thiazine, oxazole, oxadiazole,triazole or thiadiazole nuclei.

The heterocyclic saturated monocydes of the heterocycle containing anaryl moiety are, for example, tetrahydrofuran, dioxolane, imidazolidine,pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine,piperazine, trithiane, oxepine or azepine nuclei. The heterocyclecontaining an aryl moiety can contain one or more unsaturated monocydesderived from the aromatic or heterocyclic monocydes described above.

The heterocycle containing an aryl moiety is monocyclic or polycyclic,preferably bicyclic or tricyclic.

It should be understood that each of the saturated and/or unsaturatedmonocydes in the heterocycle containing an aryl moiety can besubstituted by oxo.

Examples of heterocycles containing an aryl moiety are especially thenuclei of the formulae:

in which M and T are independently chosen from O, S, SO₂, N and C, itbeing understood that each of the nuclei B1 to B12 includes at least onehetero atom optionally in oxidised form, and R is chosen from O, S andN.

According to the preferred embodiments of the invention:

T represents O, S or SO₂ and M represents N or C. Preferably, in B1, Trepresents O; in B2, T represents O or S; in B3, T represents SO₂ or Oand M represents C or N; in B4, R represents S; in B5, T represents O;in B6, T represents O; in B7, T represents O; in B8, T represents O; inB9, R represents S; in B10, T represents O; in B11, T represents O; inB12, R represents N.

When M, T or R represents N, this nitrogen is preferably substituted bya hydrogen atom, with alkyl or with alkylcarbonyl.

Preferably, the heterocycle containing an aryl moiety has the formula:

The substituents on the aryl groups, heteroaryl groups containing anaromatic moiety and heteroaryl groups are chosen from halogen atoms;cyano; nitro; optionally halogenated (C₁-C₁₄)alkoxy (and preferablytrifluoromethoxy); optionally halogenated (C₁-C₁₄)thioalkoxy, preferably(C₁-C₁₀)thioalkoxy; optionally halogenated and preferably perhalogenated(C₁-C₁₄)alkyl (especially methyl or trifluoromethyl);(C₁-C₁₄)alkylcarbonyl in which the alkyl moiety is optionallyhalogenated; (C₆-C₁₈)arylcarbonyl in which the aryl moiety is optionallysubstituted one or more times by halogen, optionally halogenated(C₁-C₁₄)alkyl and optionally halogenated (C₁-C₁₄)alkoxy;(C₁-C₁₄)alkylcarbonylamino in which the alkyl moiety is optionallyhalogenated; (C₆-C₁₈)arylcarbonylamino in which the aryl moiety isoptionally substituted one or more times by halogen, optionallyhalogenated (C₁-C₁₄)alkyl and optionally halogenated (C₁-C₁₄)alkoxy; and(C₆-C₁₈)aryl optionally substituted one or more times by halogen,optionally halogenated (C₁-C₁₄)alkyl such as trifluoromethyl, andoptionally halogenated (C₁-C₄)alkoxy such as trifluoromethoxy.

The term “halogen” especially means a chlorine, bromine, iodine orfluorine atom.

The acyl groups, heteroaryl groups and heterocyclic groups containing anaromatic moiety can be substituted one or more times by the substituentslisted above, preferably one to three times, for example one or twotimes.

The alkyl group of the alkoxycarbonyl, alkyl, arylalkyl andheteroarylalkyl radicals and also the ethylene group representing B maybe substituted by one or more radicals independently chosen fromhalogen, (C₁-C₁₄)alkoxy, (C₁-C₁₄)-thioalkoxy, cyano and nitro,preferably with one to three radicals of this type.

In a particularly preferred manner, R¹ represents benzyl optionallysubstituted on the phenyl nucleus; optionally substituted phenyl; oroptionally substituted pyridyl; the substituents on the phenyl nucleiand on the pyridyl nucleus preferably being chosen from halogen atomsand cyano, trifluoromethyl, (C₁-C₆)alkyl or (C₁-C₆)alkoxy groups or a(C₆-C₁₈)aryl group (such as phenyl), itself optionally substituted byhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CF₃ or CN.

Advantageously, R² represents optionally substituted phenyl; optionallysubstituted benzopyridine; optionally substituted benzothiazole;optionally substituted naphthyl; optionally substituted quinolyl;optionally substituted triazole; or the radical:

which is optionally substituted.

Preferred substituents of these radicals representing R² are halogenatoms or CN, CF₃, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or (C₆-C₁₈)aryl groupssuch as phenyl, itself optionally substituted by halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, CF₃ or CN.

A preferred meaning of A that may be mentioned is —COOH.

Compounds that are particularly preferred in the invention are those forwhich B represents ethylene.

Another group of preferred compounds consists of compounds in which Zrepresents S and n represents 0, 1 or 2.

The following compounds are most particularly preferred:

-   -   2-(dibenzofuran-2-yloxy)-4-m-tolylsulphanylbutyric acid    -   2-(dibenzofuran-2-yloxy)-4-(2,4-dimethylphenylsulphanyl)butyric        acid    -   4-m-tolylsulphanyl-2-(4-trifluoromethoxyphenoxy)butyric acid    -   2-(4-chlorophenoxy)-4-(2,4-dimethylphenylsulphanyl)butyric acid    -   2-(3,4-dichlorophenoxy)-4-(2,5-dimethylphenylsulphanyl)butyric        acid    -   4-(2,4-dimethylphenylsulphanyl)-2-(4-methoxyphenoxy)butyric acid    -   4-(2,4-dimethylphenylsulphanyl)-2-(4-fluorophenoxy)butyric acid    -   4-(2,4-dimethylphenylsulphanyl)-2-(3-trifluoromethylphenoxy)butyric        acid    -   4-(2,5-dimethylphenylsulphanyl)-2-(4-methoxyphenoxy)butyric acid    -   2-(4-cyanophenoxy)-4-(2,5-dimethylphenylsulphanyl)butyric acid    -   2-(4-chloro-2-methoxyphenoxy)-4-(2,5-dimethylphenylsulphanyl)butyric        acid    -   2-(4-chloro-3-ethylphenoxy)-4-(2,5-dimethylphenylsulphanyl)butyric        acid    -   2-(4-chloro-2-methoxyphenoxy)-4-(naphthalen-1-ylsulphanyl)butyric        acid    -   2-(4-chlorophenoxy)-4-(2-ethylphenylsulphanyl)butyric acid    -   4-(2-ethylphenylsulphanyl)-2-(4-methoxyphenoxy)butyric acid    -   2-(4-fluorophenoxy)-4-o-tolylsulphanylbutyric acid    -   4-(2,4-dimethylphenylsulphanyl)-2-(4-trifluoromethylphenoxy)butyric        acid    -   4-(2,5-dimethylphenylsulphanyl)-2-(4-trifluoromethylphenoxy)butyric        acid    -   4-m-tolylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid    -   4-(3-chlorophenylsulphanyl)-2-(4-trifluoromethylphenoxy)butyric        acid    -   4-o-tolylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid    -   (R)-4-o-tolylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid    -   (S)-4-o-tolylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid    -   4-phenylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid.        It should be understood that the compounds of the formulae:

-   -   in which    -   X represents S or Se; and    -   R_(a) is chosen from a halogen atom and a methyl group; and    -   R_(b) represents methyl,        are excluded from the subject of the present invention since        they have already been described, as intermediate compounds, in        Chem. Pharm. Bull. 32 (12) 4779-4785 (1984) and/or J. Org. Chem.        1983, 48, 2630-2632.

When the compound of the formula I comprises an acid function, and forexample a carboxylic function, this compound can form a salt with amineral or organic base.

As examples of salts with organic or mineral bases, mention may be madeof the salts formed with metals, and especially alkali metals,alkaline-earth metals and transition metals (such as sodium, potassium,calcium, magnesium or aluminium), or with bases such as ammonia orsecondary or tertiary amines (such as diethylamine, triethylamine,piperidine, piperazine or morpholine) or with basic amino acids, or withosamines (such as meglumine) or with amino alcohols (such as3-aminobutanol and 2-aminoethanol).

When the compound of the formula I comprises a basic function, and forexample a nitrogen atom, this compound can form a salt with an organicor mineral acid.

The salts with organic or mineral acids are, for example, thehydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogenphosphate, citrate, maleate, fumarate, 2-naphthalenesulphonate andpara-toluenesulphonate.

The invention also covers salts that allow a suitable separation orcrystallisation of the compounds of the formula I, such as the saltsobtained with chiral amines.

The invention also covers the stereoisomers of the compounds of theformula I, and also mixtures of stereoisomers in all proportions.

The compounds of the formula I may be readily prepared by carrying outany one of the following processes.

A) Preparation of the compounds of the formula I in which A representsCOOH and Z represents S with n=0.

The compounds of the formula I in which A=COOH; Z=S and n=0 mayespecially be obtained by reacting a compound of the formula II:

in which B and R¹ are as defined in claim 1, with a thiol of the formulaIII:R²—SH  III

in which R² is as defined above for formula I, in the presence of abase.

The bases that may be used are organic or mineral bases such as, forexample, a hydroxide (such as an ammonium or alkali metal hydroxide), acarbonate (such as an alkali metal or alkaline-earth metal carbonate),an alkali metal alkoxide, an organic hydride (such as alkali metalhydrides), an alkali metal amide, an alkali metal fluoride, ammoniumfluoride, ammonia, triethylamine, tributylamine, pyridine orN-methylmorpholine.

Preferred bases that will be mentioned include sodium carbonate, sodiumhydride, caesium carbonate, potassium carbonate, sodium tert-butoxideand potassium tert-butoxide.

The reaction is preferably carried out in a polar aprotic solvent, suchas a nitrile (for example acetonitrile or isobutyronitrile), an amide(such as formamide, dimethylformamide, N-methyl-2-pyrrolidinone orhexylmethylphosphorylamide, a halogenated hydrocarbon (such as methylenefluoride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or dichlorobenzene), or a mixture of these solvents in anyproportions. Advantageously, the reaction is performed indimethylformamide.

The reaction temperature will be set by a person skilled in the art as afunction of the base used, the solvent chosen and the reactivity of thecompounds present.

When the solvent used is dimethylformamide and the base is an alkalimetal carbonate or a hydride such as an alkali metal hydride, or analkali metal fluoride, the temperature is advantageously maintainedbetween 80 and 150° C. and better still between 90 and 130° C.

A reaction time of 30 minutes to 5 hours and preferably of 1 hour to 3hours is usually sufficient.

B) Preparation of the Compounds of the Formula I in which A Represents—COOH and Z Represents Se with n=0

The compounds of the formula I in which A=COOH, Z=Se and n=0 may beprepared by reacting a selenium compound of the formula IV:R²—Se—Se—R²  IV

in which R² is as defined above for formula I with a hydride such as aborohydride or aluminohydride, followed by reaction of the resultingcompound with a compound of the formula II:

in which B and R¹ are as defined above for formula I.

In the first step, the bases that may be used are especially those asdefined above. Preferred hydrides that will be used are alkali metalborohydrides such as sodium borohydride.

Solvents that may especially be used include any polar aprotic solventrecommended above for the reaction of the lactone of the formula II withthe thiol of the formula III. Dimethylformamide is a solvent that isparticularly preferred for this step.

A person skilled in the art will advantageously set the temperature forthis step between 80 and 150° C. and preferably between 90 and 130° C.,as a function of the base and the solvent selected.

Usually, the reaction time is between 30 minutes and 6 hours, forexample between 1 hour and 3 hours.

The second step, which comprises the reaction of the lactone of theformula II with the compound obtained in the preceding step, isadvantageously performed in a polar aprotic solvent preferably chosenfrom a halogenated hydrocarbon, an amide or a nitrile such as thosedefined above. More particularly, this reaction will be performed indimethylformamide.

In this case also, a reaction temperature of between 80 and 150° C. isparticularly suitable. Similarly, a reaction time of between 30 minutesand 5 hours allows the isolation of sufficient amounts of the expectedproduct of the formula I.

C) Preparation of the Compounds of the Formula I in which Z RepresentsSe or S and n is Other than 0.

The compounds of the formula I in which n is non-zero may be obtained byreacting an oxidising agent with the corresponding compound of theformula I in which n=0:

in which A, R¹, R² and B are as defined above for formula I and Zrepresents S or Se, with a suitable oxidising agent.

Among the oxidising agents that may be used, meta-chloroperbenzoic acid,the acetic acid/CrO₃ mixture, magnesium dioxide, sodium dichromatecombined with sulphuric acid, selenium dioxide, sodium hypobromite orsilver oxide may especially be selected. A preferred oxidising agentthat will be used is m-chloroperbenzoic acid (m-CPBA).

The oxidation reaction is preferably performed in a solvent chosen froma halogenated hydrocarbon (such as methylene chloride, chloroform,carbon tetrachloride, dichloroethane, chlorobenzene or adichlorobenzene), a lower alcohol chosen from C₁-C₄ alkanols and moreparticularly methanol or ethanol, or a mixture of these solvents.

When the oxidising agent chosen is m-CPBA, the process is preferablyperformed in a mixture of ethanol and dichloromethane.

It is possible to control the degree of oxidation of the final compoundby varying the amount of equivalents of oxidising agent used.

In order to prepare compounds of the formula I in which n=1, thecompound of the formula Ia will be placed in contact with not more thanabout one equivalent of m-CPBA (preferably between 0.9 and 1.1equivalents).

In order to prepare compounds of the formula I in which n=2, use will bemade of at least about 2 equivalents of m-CPBA.

The reaction is advantageously performed at a moderate temperature ofbetween 15 and 40° C., for example at room temperature, when theoxidising agent is m-CPBA.

D) Preparation of the Compounds of the Formula I in which A RepresentsAlkyloxycarbonyl or Aryloxycarbonyl

The compounds of the formula I in which A represents —COOH may bereadily converted into compounds of the formula I in which A representsalkoxycarbonyl or aryloxycarbonyl by reaction with the correspondingalkyl alcohol or aryl alcohol, respectively.

According to one preferred embodiment of the invention, it is an activederivative of the carboxylic acid of the formula I in which A=COOH thatis reacted with the alkyl alcohol or the aryl alcohol, respectively.

The activated derivative of the carboxylic acid is the correspondingcompound of the formula I in which A=—CO—K in which K is an activatinggroup for the carboxylic acid function.

Preferred activating groups that may be mentioned include chlorine,bromine, azide, imidazolide, p-nitrophenoxy, 1-benzotriazole,N—O-succinimide, acyloxy and more particularly pivaloyloxy, (C₁-C₄alkoxy)carbonyloxy such as C₂H₅CO—O—, and dialkyl- ordicydoalkyl-O-ureide.

When K═OH, the reaction of the compound of the formula I in whichA=—COOH with the alkyl alcohol or aryl alcohol, respectively, ispreferably performed in the presence of a coupling agent such as acarbodiimide, optionally in the presence of an activating agent such ashydroxybenzotriazole or hydroxysuccinimide with the intermediateformation of dialkyl- or dicycloalkyl-O-ureides. Representative couplingagents are dicyclohexyl- and diisopropylcarbodiimides, carbodiimidesthat are soluble in an aqueous medium, orbis(2-oxo-3-oxazolidinyl)phosphonyl chloride.

When K is a halogen atom, it is desirable to perform the process in thepresence of a mineral or organic base such as, for example, a hydroxide(such as an ammonium or alkali metal hydroxide), a carbonate (such as analkali metal or alkaline-earth metal carbonate), an alkali metalalkoxide, an alkali metal amide, ammonia, triethylamine, tributylamine,pyridine or N-methylmorpholine.

Another suitable base that may be used is a base supported on resin.Resins of this type are commercially available.

Examples that may be mentioned includeN,N-(diisopropyl)aminomethylpolystyrene and morpholinomethylpolystyreneresins.

The reaction is preferably performed in a solvent.

In certain cases, the base can serve as solvent. This case, for example,for pyridine.

As a variant, it is advantageous to select a polar aprotic solvent, andfor example a halogenated hydrocarbon such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or adichlorobenzene, dichloroethane being particularly preferred.

E) Preparation of the Compounds of the Formula I in which A Represents—CONH—OH

The compounds of the formula I in which A represents CONH—OH may beobtained from the corresponding compounds of the formula I in which Arepresents —COOH by the action of hydroxylamine, this reaction beingperformed in a manner that is known per se, using known techniques oforganic chemistry.

According to one particularly preferred embodiment of the invention,this reaction is performed in two steps.

In a first step, the function A=COOH is activated. To do this, anyactivated carboxylic acid derivative may be prepared (formula I in whichA=—COK) described above in step D.

Preferably, the activated derivative is an acid chloride, a carbodiimideor a mixed anhydride.

In a second step, the said activated derivative is reacted withhydroxylamine in the presence of a base, for example one of the basesdefined in step D above. Advantageously, the base is triethylamine orN-methylmorpholine.

This step is preferably performed in a polar aprotic solvent such as ahalogenated hydrocarbon (and especially dichloromethane), an ether (andespecially tetrahydrofuran) or an amide (and especiallydimethylformamide).

F) Preparation of the Compounds of the Formula I in which A RepresentsTetrazolyl

The compounds of the formula I in which A represents tetrazolyl arereadily prepared from the corresponding compounds of the formula I inwhich A represents —COOH by carrying out a two-step process.

In a first step, the corresponding amide of the formula IX is prepared:

from the carboxylic acid of the formula Ib below:

in which R¹, B, Z, n and R² are as defined above for formula I.

The conversion of compound Ib into an amide may be performed in anymanner, and for example by the action:

-   -   a- of ammonia in methanol in the presence of a Dowex 50W×8        resin;    -   b- of ethyl chloroformate and ammonia;    -   c- of SO₂(NH₂)₂ in pyridine; or    -   d- of thionyl chloride and ammonium hydroxide in 1,4-dioxane.

In a second step, the amide of the formula IX is reacted with an alkalimetal azide (such as sodium azide), in the presence oftetrachlorosilane.

This step is performed, for example, in a nitrile as solvent, such asacetonitrile or isobutyronitrile, preferably acetonitrile.

To establish the operating conditions, a person skilled in the art mayrefer to the studies by El-Ahl, A. A. S; Elmorsy S. S. et al. publishedin Tetrahedron Letters, 1997, 38(7), 1257.

The lactones of the formula II:

in which B and R¹ are as defined above for formula I may be obtained byreacting a corresponding α-halolactone of the formula V:

in which Hal represents a halogen atom preferably chosen from chlorine,bromine and iodine (bromine being more particularly preferred),

with the appropriate alcohol of the formula VI:R¹—OH  VIin the presence of an organic or mineral base.

As a variant, it is possible to synthesise the intermediate compounds ofthe formula II by the action of the corresponding α-hydroxylactone ofthe formula VII:

on the appropriate halide of the formula VIII:R¹-Hal  VIIIin which formulae R¹ and B are as defined for formula I and Hal is ahalogen atom preferably chosen from chlorine, bromine and iodine(bromine being more particularly preferred), this reaction beingperformed in the presence of an organic or mineral base.

The bases that may be used in the preparation of compounds of theformula II are those generally defined above.

In the case of the first variant (reaction of V with VI), it ispreferred to use an alkali metal carbonate (such as caesium carbonate)or an alkali metal alkoxide (such as sodium ethoxide) as base.

In the case of the second variant, a base such as an alkali metalhydride and especially sodium hydride is particularly suitable.

The operating conditions, and especially the reaction temperature andthe solvent, depend especially on the type of base used.

In the first variant (reaction of V with VI), the process is preferablyperformed:

-   -   either in a ketone (such as acetone), in the presence of an        alkali metal carbonate such as caesium carbonate, at a        temperature of between 40 and 100° C. and better still between        50 and 70° C.;    -   or in a lower alcohol (such as a C₁-C₄ alkanol of the type such        as ethanol) in the presence of the corresponding alkali metal        alkoxide, at a temperature of between 40 and 120° C., for        example between 50 and 100° C. and more particularly between 60        and 80° C.

In the second variant, preferred conditions are the use of an alkalimetal hydride such as a sodium hydride, the choice of an amide assolvent and advantageously dimethylformamide, at a temperature rangingbetween −5 and 45° C. According to one preferred embodiment of theinvention, the base is reacted with the α-hydroxylactone at lowtemperature (between −5 and +10° C.), followed by addition to thereaction medium of the halide of the formula VIII, leaving it to reactat a temperature generally of between 15 and 45° C., for example at roomtemperature, for the time required for the reaction.

The enantiomers of the compounds of the formula I that contain anasymmetric carbon a to the group A:

may be prepared from the corresponding enantiomeric lactones of theformula II:

in which the carbon labelled with the asterisk has the sameconfiguration as the corresponding carbon in formula Ib above, bycarrying out the same type of reaction as described above in A).

One method for preparing the optically active compounds of the formulaII is as follows.

The alcohol of the formula VI, R₁OH, is reacted with an optically activeα-hydroxylactone of the formula VIIa:

in which B is as defined above for formula I in the presence of diethylazodicarboxylate and triphenylphosphine.

Ideally, the reaction is carried out in a polar aprotic solvent such asan ether of the type such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether. As a variant, a halogenated hydrocarbon such as methylenechloride, chloroform, carbon tetrachloride, dichloroethane,chlorobenzene or a dichlorobenzene may be used.

Since this reaction takes place with inversion of stereochemistry at theendocydic asymmetric carbon, bearing the —OH group, the o-hydroxylactoneof the formula VIIa, which is of opposite configuration relative to theconfiguration of the corresponding carbon in formula II, will beselected.

Schematically:

The invention also relates to pharmaceutical compositions comprising apharmaceutically effective amount of a compound of the formula (I) asdefined above in combination with one or more pharmaceuticallyacceptable vehicles.

These compositions may be administered orally in the form of tablets,gel capsules or granules with immediate release or sustained release,intravenously in the form of an injectable solution, transdermally inthe form of an adhesive transdermal device, or locally in the form of asolution, cream or gel.

The pharmaceutical compositions of the present invention may also beadministered by nasal aerosol or inhalation through the use of anebulizer, a dry powder inhaler or a metered dose inhaler. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and may be prepared as solutions insaline, employing benzyl alcohol or other suitable preservatives,absorption promoters to enhance bioavailability, hydrofluorocarbons,and/or other conventional solubilizing or dispersing agents.

A solid composition for oral administration is prepared by adding to theactive principle a filler and, where appropriate, a binder, adisintegrating agent, a lubricant, a colorant or a flavour enhancer, andby placing the mixture in the form of a tablet, a coated tablet, agranule, a powder or a capsule.

Examples of fillers include lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide, and examples ofbinders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose,methylcellulose, acacia, gum tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate,dextrin and pectin. Examples of lubricants include magnesium stearate,talc, polyethylene glycol, silica and hardened plant oils. The colorantmay be any of those permitted for used in medicaments. Examples offlavour enhancers include cocoa powder, mint in herb form, aromaticpowder, mint in oil form, borneol and cinnamon powder. Obviously, thetablet or granule may be suitably coated with sugar, gelatin or thelike.

An injectable form containing the compound of the present invention asactive principle is prepared, where appropriate, by mixing the saidcompound with a pH regulator, a buffer agent, a suspension agent, asolubiliser, a stabiliser, an isotonic agent and/or a preserving agent,and by converting the mixture into a form for intravenous, subcutaneousor intramuscular injection, according to a standard process. Whereappropriate, the injectable form obtained may be freeze-dried by astandard process.

Examples of suspension agents include methylcellulose, polysorbate 80,hydroxyethylcellulose, acacia, powdered gum tragacanth, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilisers include castor oil solidified withpolyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitanmonolaurate and the ethyl ester of castor oil fatty acid.

In addition, the stabiliser encompasses sodium sulphite, sodiummetasulphite and ether, while the preserving agent encompasses methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic],cresol and chlorocresol.

The invention is also directed towards the use of an active principlechosen from a compound of the formula (I) as defined above, for thepreparation of a medicament intended for preventing or treatingdyslipidaemia, atherosclerosis and diabetes.

In the above description of pharmaceutical compositions containing apreferred compound, the equivalent expressions: “administration”,

“administration of”, “administering”, and “administering a” have beenused with respect to said pharmaceutical compositions. As thus employed,these expressions are intended to mean providing to a patient in need oftreatment a pharmaceutical composition of the present invention by anyof the routes of administration herein described, wherein the activeingredient is a preferred compound or a prodrug, derivative, ormetabolite thereof which is useful in treating a disease, disorder, orcondition mediated by or associated with modulation of activation ofPPARα and PPARγ isoforms in said patient. Accordingly, there is includedwithin the scope of the present invention any other compound which, uponadministration to a patient, is capable of directly or indirectlyproviding a preferred compound. Such compounds are recognized asprodrugs, and a number of established procedures are available forpreparing such prodrug forms of the preferred compounds.

The dosage and dose rate of the compounds effective for treating orpreventing, a disease, disorder, or condition mediated by or associatedwith modulation of activation of PPARα and PPARγ isoforms, will dependon a variety of factors, such as the nature of the activator, the sizeof the patient, the goal of the treatment, the nature of the pathologyto be treated, the specific pharmaceutical composition used, and theobservations and conclusions of the treating physician.

For example, where the dosage form is oral, e.g., a tablet or capsule,suitable dosage levels of the compounds of formula I will be betweenabout 0.1 μg/kg and about 50.0 mg/kg of body weight per day, preferablybetween about 5.0 μg/kg and about 5.0 mg/kg of body weight per day, morepreferably between about 10.0 μg/kg and about 1.0 mg/kg of body weightper day, and most preferably between about 20.0 μg/kg and about 0.5mg/kg of body weight per day of the active ingredient.

Where the dosage form is topically administered to the bronchia andlungs, e.g., by means of a powder inhaler or nebulizer, suitable dosagelevels of the compounds will be between about 0.001 μg/kg and about 10.0mg/kg of body weight per day, preferably between about 0.5 μg/kg andabout 0.5 mg/kg of body weight per day, more preferably between about1.0 μg/kg and about 0.1 mg/kg of body weight per day, and mostpreferably between about 2.0 μg/kg and about 0.05 mg/kg of body weightper day of the active ingredient.

Using representative body weights of 10 kg and 100 kg in order toillustrate the range of daily oral dosages which might be used asdescribed above, suitable dosage levels of the compounds of formula Iwill be between about 1.0-10.0 μg and 500.0-5000.0 mg per day,preferably between about 50.0-500.0 μg and 50.0-500.0 mg per day, morepreferably between about 100.0-1000.0 μg and 10.0-100.0 mg per day, andmost perferably between about 200.0-2000.0 μg and about 5.0-50.0 mg perday of the active ingredient comprising a preferred compound. Theseranges of dosage amounts represent total dosage amounts of the activeingredient per day for a given patient. The number of times per day thata dose is administered will depend upon such pharmacological andpharmacokinetic factors as the half-life of the active ingredient, whichreflects its rate of catabolism and clearance, as well as the minimaland optimal blood plasma or other body fluid levels of said activeingredient attained in the patient which are required for therapeuticefficacy.

The activity of the compounds of the invention leading to ahypolipidaemiant and hypoglycaemiant effect was demonstrated in vitroand in vivo by carrying out the following tests.

The measurement of the PPAR activation was performed according to atechnique described by Lehmann et al. (1995, J. Biol. Chem. 270:12953-12956).

CV-1 cells (monkey kidney cells) are co-transfected with an expressionvector for the chimeric proteins PPARα-Gal4 or PPARγ-Gal4 and with a“reporter” plasmid which allows the expression of the luciferase geneplaced under the control of a promoter containing Gal4 responseelements.

The cells are inoculated in 96-zwell microplates and co-transfectedusing a commercial reagent with the reporter plasmid (pG5-tk-pGL3) andthe expression vector for the chimeric protein (PPARα-Gal4 orPPARγ-Gal4). After incubating for 4 hours, whole culture medium(containing 10% foetal calf serum) is added to the wells. After 24hours, the medium is removed and replaced with whole medium containingthe test products (50 μM final). The products are left in contact withthe cells for 18 hours. The cells are then lysed and the ludferaseactivity is measured using a luminometer. A PPAR activation factor canthen be calculated by means of the activation of the expression of thereporter gene induced by the product (relative to the control cells thathave not received any product).

By way of example, the compound of Example 5, at a concentration of 50μM, activates the chimeric protein PPARα-Gal-4 by factor of nine, andthe chimeric protein PPARγ-Gal4 by a factor of six. In the absence ofthe binding region for the PPARα or γ ligand (vector expressing Gal4alone), the luciferase activity measured in the presence of this productis zero.

The antidiabetic and hypolipidaemiant activity of the compounds wasdetermined orally in db/db mice.

16 week-old db/db mice are treated orally for 15 days with the compoundof Example 5 (20 mg/kg/day). Each group studied comprises seven animals.After treatment for 15 days, retro-orbital samples are taken after amild anaesthesia and fasting for 4 hours.

The following parameters were measured:

Glycaemia assay (glucose oxidase) and assay of the lipid parameters onthe sera at D15 (COBAS): triglycerides, total cholesterol (CHOL), theHDL cholesterol (HDL-C) and the free fatty acids (FFA) (BioMérieux andWaco Chemicals assay kit).

The results obtained are collated in the following table. Themeasurements given represent mean values±standard error.

% variation relative Control Example 5 to the control Glycaemia mM 27.1± 7.0 11.1 ± 3.3  −59* Triglycerides mM  1.3 ± 0.3 0.7 ± 0.1 −47* HDL-CmM  3.2 ± 0.2 4.3 ± 0.6   36* CHOL mM 3.65 ± 0.2 5.4 ± 0.9   47* FFA mM 0.7 ± 0.1 0.4 ± 0.0 −38* % var: percentage of variation versus control.Mann-Whitney Test: *, p < 0.05 vs control

These results demonstrate the antidiabetic and hypolipidaemiant activityof the compounds of the invention on triglycerides and free fatty acids.The marked increase in the level of HDL cholesterol by these samecompounds should be noted.

The examples that follow illustrate invention in a non-limiting manner.

In the proton nuclear magnetic resonance data (300 MHz NMR), thefollowing abbreviations have been used: s for singlet, d for doublet, tfor triplet, q for quartet, o for octet and m for complex multiplet. Thechemical shifts δ are expressed in ppm; m.p. represents the meltingpoint.

Preparation 1: 3-(4-fluorophenoxy)dihydrofuran-2-one

α-Bromobutyrolactone (12.4 g, 0.075 mol) is added to a mixture of4-fluorophenol (5.6 g, 0.05 mol) and caesium carbonate (17.9 g, 0.055mol) in acetone (100 ml). The reaction medium is refluxed for two hours.After cooling to room temperature, the reaction is filtered through abed of Celite and the filtrate is evaporated. The oily residue ispurified by flash chromatography (1/2 EtOAc/heptane) to give theexpected product in the form of an oil (9.8 g, 87%).

¹H NMR (CDCl₃, 300 MHz): 2.4 (1H, m), 2.65 (1H, m), 4.3 (1H, m), 4.8(1H, m), 4.8 (1H, t, J=7.5 Hz), 6.95 (4H, m).

Preparation 2: 3-(4-bromophenoxy)dihydrofuran-2-one

Sodium (23 g, 1 mol) is added in pieces to a reactor containing ethanol(1 l). The temperature of the reaction medium is stabilised at 70° C.(exothermic) before adding a solution of 4-bromophenol (173 g, 1 mol) inethanol (150 ml). After cooling to room temperature,α-bromo-γ-butyrolactone (83 ml, 1 mol) is added slowly. The reactionmedium is stirred for ten hours and is then treated by adding 1Nhydrochloric acid solution (600 ml). The aqueous phase is extracted withethyl acetate (2×1 l) and the combined organic phases are washed withwater (1 l), dried over sodium sulphate, filtered and concentrated. Theresidue obtained is recrystallised from isopropanol (2.2 l) to give theexpected compound in the form of a white powder (80.1 g, 31%).

m.p: 90° C. IR: 1690, 1770, 1790. ¹H NMR (CDCl₃, 300 MHz): 2.5 (1H, m),2.7 (1H, m), 4.4 (1H, m), 4.5 (1H, m), 4.9 (1H, t, J=7.5 Hz), 6.9 (2H,m), 7.4 (2H, m).

Preparation 3: 3-(4-trifluoromethylphenoxy)dihydrofuran-2-one

The compound is prepared according to the experimental proceduredescribed in Preparation 1, starting with α-bromo-γ-butyrolactone (6.7g, 0.040 mol) and 4-trifluoromethylphenol (5.0 g, 0.031 mol) to give3.51 g of the expected compound in the form of a white powder.

m.p.: 84-86° C.; ¹H NMR (DMSO-d6, 300 MHz): 2.20-2.45 (1H, m), 2.70-2.90(1H, m), 4.20-4.53 (2H, m), 5.51 (1H, t, J=9.0 Hz), 7.74 (2H, d, J=8.9Hz), 7.69 (2H, d, J=8.9 Hz).

Preparation 4: 3-(biphenyl-2-ylmethoxy)dihydrofuran-2-one

Sodium hydride (0.43 g, 10.8 mmol) is added portionwise to a solution ofα-hydroxy-γ-butyrolactone (1 g, 9.8 mmol) in DMF (15 ml) at 0° C. undera nitrogen atmosphere. 2-Bromomethylbiphenyl (2.42 g, 9.8 mmol) is thenrapidly added. The reaction medium is stirred for 2 hours at roomtemperature and is then treated by adding 1N hydrochloric acid solution(10 ml). The aqueous phase is extracted with ethyl acetate (2×20 ml) andthe combined organic phases are washed with water (4×15 ml), dried oversodium sulphate, filtered and concentrated. After purification by flashchromatography (2/1 heptane/EtOAc), the expected compound is obtained inthe form of a colourless oil (1.32 g, 50%).

¹H NMR (CDCl₃, 300 MHz): 2.00-2.35 (2H, m), 3.85-4.00 (1H, m), 4.00-4.15(1H, m), 4.15-4.30 (1H, m), 4.40-4.80 (2H, m), 7.10-7.40 (8H, m),8.40-8.60 (1H, m).

Preparation 5: (S)-3-(4-trifluoromethylphenoxy)dihydrofuran-2-one

Diethyl azodicarboxylate (2.31 ml, 14.7 mmol) is slowly added to asolution of (R)-(+)-α-hydroxy-γ-butyrolactone (1 g, 9.8 mmol),4-trifluoromethylphenol (1.58 g, 9.8 mmol) and triphenylphosphine (3.86g, 14.7 mmol) in anhydrous THF (80 ml) cooled to 0° C. After stirringfor 5 minutes at 0° C. and overnight at room temperature, the solvent isevaporated off and the triphenylphosphine oxide is then precipitatedfrom ether and filtered off. The filtrate is then washed with water,dried over magnesium sulphate and evaporated. After purification byflash chromatography (3/1 heptane/EtOAc), the expected compound isobtained in the form of a white powder (1.14 g, 47%).

¹H NMR (DMSO-d6, 300 MHz): 2.20-2.45 (1H, m), 2.70-2.90 (1H, m),4.20-4.53 (2H, m), 5.51 (1H, t, J=9.0 Hz), 7.74 (2H, d, J=8.9 Hz), 7.69(2H, d, J=8.9 Hz).

Preparation 6: (R)-3-(4-trifluoromethylphenoxy)dihydrofuran-2-one

The compound is prepared according to the experimental proceduredescribed, starting with (S)-(−)-α-hydroxy-γ-butyrolactone (2 g, 19.6mmol) and 4-trifluoroethylphenol (3.18 g, 19.6 mmol) to give 1.7 g (35%)of the expected compound in the form of a white powder.

¹H NMR (DMSO-d6, 300 MHz): 2.20-2.45 (1H, m), 2.70-2.90 (1H, m),4.20-4.53 (2H, m), 5.51 (1H, t, J=9.0 Hz), 7.74 (2H, d, J=8.9 Hz), 7.69(2H, d, J=8.9 Hz).

EXAMPLE 1 2-(4-fluorophenoxy)-4-phenylsulphanylbutyric acid

A 1 N solution of sodium tert-butoxide in DMF (0.2 ml, 0.2 mmol) isadded to a solution of thiophenol (25 mg, 0.23 mmol) in DMF (1 ml).After stirring for 15 minutes at room temperature, a solution ofpreparation 1 (30 mg, 0.15 mmol) in DMF (1 ml) is added and the mixtureis heated at 120° C. for 1 hour. After cooling to room temperature, thereaction is treated with 1N hydrochloric add (1 ml) and the product isextracted with ethyl acetate (3 ml). The organic phase is washed withwater (3×2 ml) and is then concentrated until a volume of 1 ml isobtained. This solution is purified by flash chromatography (2/1heptane/EtOAc) to give the expected compound in the form of a whitepowder (27 mg, 57%).

¹H NMR (CDCl₃, 300 MHz): 2.35 (2H, m), 3.0 (2H, m), 4.7 (1H, dd, J=9.5Hz), 6.75 (1H, m), 6.95-6.8 (3H, m), 7.0 (2H, m); MS AP⁻ (M−1)=305.

EXAMPLE 2 2-(4-bromophenoxy)-4-o-tolylsulphanylbutyric acid

The compound is prepared according to the experimental proceduredescribed in Example 1, starting with the compound of preparation 2 (2g, 7.8 mmol) and ortho-thiocresol (1.38 ml, 11.6 mmol) to give thecompound of Example 2 in the form of an oil that crystallises onstanding (2.3 g, 77%).

m.p.: 96-98° C.; ¹H NMR (CDCl₃, 300 MHz): 2.2 (2H, m), 2.3 (3H, s), 3.1(2H, m), 4.8 (1H, dd, J=3.5 and 9.5), 6.7 (2H, m), 7.1 (2H, m), 7.2 (2H,m), 7.3 (2H, d, J=9 Hz).

EXAMPLE 3 4-o-tolylsulphanyl-2-(4-trifluoromethylphenoxy)butyric add

The compound is prepared according to the experimental proceduredescribed in Example 1, starting with the compound of preparation 3 (6.7g, 0.040 mol) and ortho-thiocresol (1.38 ml, 11.6 mmol) to give 3.51 gof the expected compound in the form of a white powder.

¹H NMR (CDCl₃, 300 MHz): 2.20-2.50 (3H, s+2H, m); 3.00-3.25 (2H, m);4.94 (1H, m); 6.85-7.00 (2H, m); 7.00-7.20 (3H, m); 7.20-7.40 (1H, m)7.50-7.65 (2H, m), (N.B.: acid OH not observed).

EXAMPLE 4 2-(biphenyl-2-ylmethoxy)-4-phenylsulphanylbutyric acid

Sodium hydride (60% dispersion) (12 mg, 0.9 mmol) is added to a solutionof thiophenol (100 mg, 0.9 mmol) in DMF (1 ml) at room temperature.After stirring for 30 minutes, a solution of the compound of preparation4 (52 mg, 0.2 mmol) in DMF (1 ml) is added and the temperature of thereaction medium is maintained at 120° C. for 3 hours. After cooling toroom temperature, the reaction is treated with 1N hydrochloric acid (2ml) and the product is extracted with ethyl acetate (3 ml). The organicphase is washed with water (3×3 ml) and is then dried over magnesiumsulphate, filtered and evaporated. After purification by flashchromatography (heptane), the expected compound is obtained in the formof a colourless oil (50 mg, 69%).

¹H NMR (DMSO-d6, 300 MHz): 1.80-2.00 (2H, m); 2.85-3.10 (2H, m); 3.95(1H, m); 4.20-4.60 (2H, m); 7.10-7.30 (6H, m); 7.30-7.50 (7H, m);7.50-7.60 (1H, m); 12.83 (1H, exchangeable, broad s).

EXAMPLE 5 4-phenylsulphanyl-2-(4-trifluoromethylphenoxy)butyric acid

The compound is prepared according to the experimental proceduredescribed for Example 1, starting with the compound of preparation 3(6.7 g, 0.040 mol) and thiophenol (1.38 ml, 11.6 mmol) to give 3.51 g ofthe expected compound in the form of a white powder.

m.p.: 108-110° C.; ¹H NMR (DMSO-d6, 300 MHz): 2.10-2.30 (2H, m);3.00-3.20 (2H, m); 5.00 (1H, m); 7.00-7.10 (2H, m); 7.10-7.60 (5H, m);7.60-7.80 (2H, m); 13.35 (1H, exchangeable, broad s); MS AP− (M−1)=355.

EXAMPLE 6 4-phenylselanyl-2-(4-trifluoromethylphenoxy)butyric acid

Sodium borohydride (30 mg, 0.8 mmol) is added to a solution of diphenyldiselenide (111 mg, 0.35 mmol) in DMF (1.5 ml) at room temperature. Themixture is heated at 100° C. for 20 minutes, followed by addition of asolution of the compound of preparation 3 (160 mg, 0.65 mmol) in DMF (1ml). The reaction mixture is then heated at 120° C. for 2.5 hours. Aftercooling to room temperature, the reaction medium is treated with 10%hydrochloric acid (1 ml) and the product is extracted with ethyl acetate(4 ml). The organic phase is washed with water (3×2 ml) and is thendried over magnesium sulphate, filtered and evaporated. Afterpurification by flash chromatography (2/1 heptane/EtOAc), the expectedcompound is obtained in the form of a white powder (176 mg, 67%).

¹H NMR (CDCl₃, 300 MHz): 2.20-2.55 (2H, m); 2.90-3.30 (2H, m); 4.92 (1H,m); 6.80-7.00 (2H, m); 7.10-7.30 (3H, m); 7.40-7.60 (4H, m); (N.B.: acidOH not observed).

EXAMPLE 7 Methyl4-(toluene-2-sulphanyl)-2-(4-trifluoromethylphenoxy)butyrate

A catalytic amount of H₂SO₄ (2 drops) is added to a solution of thecompound of Example 3 (5.14 g, 13.9 mmol) in methanol (40 ml). Thereaction is refluxed for 12 hours. The solvent is then evaporated offunder vacuum, the residue is taken up in ethyl acetate (50 ml) and theorganic phase is washed with water (2×50 ml), dried over sodiumsulphate, filtered and concentrated. After purification by flashchromatography (1/5 EtOAc/heptane), the compound of Example 7 isobtained in the form of a yellow oil (5 g, 93%).

¹H NMR (CDCl₃): 2.11-2.44 (5H, m); 2.96-3.21 (2H, m); 3.74 (3H, s);4.80-4.97 (1H, m); 6.84-6.97 (2H, m); 7.03-7.33 (4H, m); 7.47-7.58 (2H,m).

EXAMPLE 8 4-o-tolylsulphanyl-2-(S)-(4-trifluoromethylphenoxy)butyricacid

Caesium carbonate is added to a solution of ortho-thiocresol (66 mg,0.53 mmol) in anhydrous DMF (1 ml) under nitrogen. After stirring for 15minutes at room temperature, a solution of the compound of preparation 5(100 mg, 0.4 mmol) in anhydrous DMF (1 ml) is added and the reactionmedium is heated at 120° C. for one hour. After cooling to roomtemperature, the reaction is treated with 1N hydrochloric acid (1 ml)and the product is extracted with ethyl acetate (3 ml). The organicphase is washed with water (3×2 ml) and is then concentrated until avolume of 1 ml is obtained. This solution is purified by flashchromatography (2/1 heptane/EtOAc) to give the compound of Example 8 inthe form of a white powder (93 mg, 62%).

[α]_(D)=−32.5 (c=0.5, MeOH)

¹H NMR (CDCl₃, 300 MHz): 2.20-2.50 (3H, s+2H, m); 3.00-3.25 (2H, m);4.94 (1H, m); 6.85-7.00 (2H, m); 7.00-7.20 (3H, m); 7.20-7.40 (1H, m)7.50-7.65 (2H, m) (N.B.: acid OH not observed).

EXAMPLE 9 4-o-Tolylsulphanyl-2-(R)-(4-trifluoromethylphenoxy)butyricacid

The compound is prepared according to the experimental proceduredescribed for Example 8, starting with the compound of preparation 6(100 mg, 0.4 mmol) and ortho-thiocresol (66 mg, 0.53 mmol) to give 90 mgof the expected compound in the form of a white powder.

[α]_(D)=+33.0 (c=0.5, MeOH) ¹H NMR (CDCl₃, 300 MHz): 2.20-2.50 (3H,s+2H, m); 3.00-3.25 (2H, m); 4.94 (1H, m); 6.85-7.00 (2H, m); 7.00-7.20(3H, m); 7.20-7.40 (1H, m); 7.50-7.65 (2H, m) N.B.: acid OH notobserved.

EXAMPLE 10 Methyl4-(toluene-2-sulphonyl)-2-(4-trifluoromethylphenoxy)butyrate

70% MCPBA (1.49 g, 3.9 mmol) is added to a solution of the compound ofExample 7 (500 mg, 1.3 mmol) in CH₂Cl₂ (10 ml) at 0° C. The reaction isstirred at room temperature for one hour. The reaction is then dilutedwith CH₂Cl₂ (10 ml) and poured into saturated sodium bisulphite solution(20 ml). The organic phase is washed with saturated NaHCO₃ solution(2×20 ml), H₂O (20 ml), dried over sodium sulphate, filtered andconcentrated. The compound of Example 10 is obtained in the form of acolourless oil (540 mg, 99%).

¹H NMR (CDCl₃): 2.21-2.59 (2H, m); 2.67 (3H, s); 3.21-3.51 (2H, m); 3.74(3H, s); 4.73-4.95 (1H, m); 6.72-6.95 (2H, m); 7.26-7.62 (5H, m);7.79-8.09 (1H, m), MS ES+(M+1)=417

EXAMPLE 11 Methyl4-(toluene-2-sulphinyl)-2-(4-trifluoromethylphenoxy)butyrate

A 13% sodium hypochlorite solution (0.246 ml, 0.250 mmol) is added to asolution of the compound of Example 7 (200 mg, 0.520 mmol) in methanol(4 ml) at −78° C. The reaction is stirred at −78° C. for 1 hour. Themethanol is then evaporated off, the residue is taken up in ethylacetate (5 ml) and the organic phase is washed with 1N hydrochloric acidsolution (3 ml), with water (3 ml), filtered through a filter membrane(porosity 5 μm) and concentrated. After purification by flashchromatography (1/2 EtOAc/heptane and then 1/2/2 MeOH/EtOAc/heptane),the compound of Example 11 is obtained in the form of a colourlessamorphous product (60 mg, 29%).

¹H NMR (CDCl₃): 1.93-2.70 (5H, m); 2.70-3.22 (2H, m); 3.73 and 3.75 (3H,2s); 4.65-4.99 (1H, m); 6.72-7.04 (2H, m); 7.07-7.63 (5H, m); 7.75-8.00(1H, m), MS ES+(M+1)=401

EXAMPLE 12 4-(Toluene-2-sulphonyl)-2-(4-trifluoromethylphenoxy)butyricacid

A 1N sodium hydroxide solution (0.7 ml, 0.7 mmol) is added dropwise to asolution of the compound of Example 10 (220 mg, 0.53 mmol) in THF (5 ml)at 0° C. The reaction is stirred at room temperature for 1 hour. The THFis evaporated off; the residue is taken up in ethyl acetate (5 ml) andthe organic phase is washed with 1N hydrochloric acid solution (3 ml),with water (4 ml), dried over sodium sulphate, filtered and evaporatedto give the compound of Example 12 (210 mg, 99%) in the form of acolourless amorphous product.

¹H NMR (CDCl₃): 2.29-2.70 (5H, m); 3.22-3.54 (2H, m); 4.76-5.01 (1H, m);6.54 (1H, broad s); 6.78-6.97 (2H, m); 7.19-7.43 (2H, m); 7.43-7.63 (3H,m); 7.87-8.08 (1H, m), MS ES−(M−1)=401

EXAMPLE 13 4-(Toluene-2-sulphinyl)-2-(4-trifluoromethylphenoxy)butyricacid

A 1N sodium hydroxide solution (0.2 ml, 0.2 mmol) is added dropwise to asolution of the compound of Example 11 (60 mg, 0.12 mmol) in ThF (2 ml)at 0° C. The reaction is stirred at room temperature for 1 hour and thenat 50° C. for a further one hour. The THF is evaporated off; the residueis taken up in ethyl acetate (5 ml) and the organic phase is washed with1N hydrochloric acid solution (3 ml), with water (4 ml), dried oversodium sulphate, filtered and evaporated to give the compound of Example12 (210 mg, 99%) in the form of a colourless amorphous product.

¹H NMR (CDCl₃): 2.06-2.69 (5H, m); 2.87-3.32 (2H, m); 4.67-5.15 (1H, m);5.80 (1H, broad s); 6.81-7.04 (2H, m); 7.14-7.33 (1H, m); 7.33-7.60 (4H,m); 7.79-7.99 (1H, m), MS ES−(M−1)=385

Synthesis of compounds from examples 10-13 is outlined in the followingscheme:

Table I below illustrates Examples 10 to 60, which are compounds of theformula I in which A represents —COOH and B represents —CH₂—CH₂.

TABLE 1 Ex. R¹ R² Z n Characterisation data 1 p-fluorophenyl phenyl S 0CDCl₃: 2.35(2H, m), 3.0 (2H, m), 4.7(1H, dd, J=9.5 Hz), 6.75(1H, m),6.95-6.8 (3H, m), 7.0(2H, m), 2 p-bromophenyl 2-methylphenyl S 0 CDCl₃:2.15-2.20(3H, s+2H.m); 3.00-3.25(2H, m); 4.82(1H, m); 6.70-6.90(2H, m);7.00-7.50(6H, m)(N.B.: acid OH not observed) 3 4-trifluoromethyl-phenyl2-methylphenyl S 0 DMSO-d6: CDCl₃: 2.20- 2.50(5H, m); 3.00-3.25(2H, m);4.94(1H, m); 6.90-7.00 (2H, m); 7.00-7.20(3H, m); 7.20-7.35(1H.m);7.45-7.65 (2H.m)(N.B.: acid OH not observed) 4 o-phenylbenzyl phenyl S 0DMSO-d6: 1.80-2.00(2H, m); 2.85-3.10(2H, m); 3.95 (1H, m); 4.20-4.60(2H,m); 7.10-7.30(6H.m); 7.30-7.50 (7H, m); 7.50-7.60(1H, m); 12.83(1H,exchangeable, broad s) 5 4-trifluoromethyl-phenyl phenyl S 0 DMSO-d6:2.10-2.30(2H, m); 3.00-3.20(2H, m); 5.00 (1H, m); 7.00-7.10(2H, m);7.10-7.60(5H, m); 7.60-7.80 (2H, m); 13.35(1H, exchangeable, broad s) MSAP−(M−1)=355 6 4-trifluoromethyl-phenyl phenyl Se 0 CDCl₃: 2.20-2.55(2H,m); 2.90-3.30(2H, m); 4.92(1H, m); 6.80-7.00(2H, m); 7.10- 7.30(3H, m);7.40-7.60(4H, m); (N.B.: acid OH not observed) 74-trifluoromethyl-phenyl 2-methylphenyl S 2 CDCl₃: 2.25-2.80(3H, s+ 2H,m); 3.20-3.60(2H, m); 4.88(1H, m); 6.85-7.20(3H, m); 7.20-7.45(1H, m);7.45- 7.70(3H.m); 7.80-8.15(1H, m); (N.B.: acid OH not observed). MSES−(M−1)=401 8 4-trifluoromethyl-phenyl 2-methylphenyl S 0 CDCl₃:2.20-2.50(3H, s+ 2H, m); 3.00-3.25(2H, m); 4.94(1H, m); 6.85-7.00(2H,m); 7.00-7.20(3H, m); 7.20- 7.40(1H, m)7.50-7.65(2H, m)(N.B.: acid OHnot observed) 9 4-trifluoromethyl-phenyl 2-methylphenyl S 0 CDCl₃:2.20-2.50(3H, s+ 2H, m); 3.00-3.25(2H, m); 4.94(1H, m); 6.85-7.00(2H,m); 7.00-7.20(3H, m); 7.20- 7.40(1H, m)7.50-7.65(2H, m)(N.B.: acid OHnot oberved) 10 4-tert-butylbenzyl phenyl S 0 MS AP+(M+1)=359 114-tert-butylbenzyl 3-methoxyphenyl S 0 MS AP+(M+1)=389 124-tert-butylbenzyl 4-fluorophenyl S 0 MS AP+(M+1)=377 134-tert-butylbenzyl

S 0 MS AP+(M+1)=503 14 4-chlorophenyl phenyl S 0 MS AP−(M−1)=321 154-chlorophenyl 3-methoxyphenyl S 0 DMSO-d6: 2.00-2.20(2H, m);3.00-3.20(2H, m); 3.74 (3H, s); 4.85(1H, m); 6.60- 6.85(1H, m);6.85-7.10(4H, m); 7.10-7.40(3H, m); 2.06- 14.00(1H, exchangeable, broads) MS AP−(M−1)=351 16 4-chlorophenyl 4-fluorophenyl S 0 MS AP−(M−1)=34017 4-chlorophenyl

S 0 MS AP−(M−1)=466 18 4-trifluoromethyl-phenyl 3-methoxyphenyl S 0 MSAP−(M−1)=385 19 4-trifluoromethyl-phenyl 4-fluorophenyl S 0 MSAP−(M−1)=373 20 4-trifluoromethyl-phenyl

S 0 DMSO-d6: 2.20-2.40(2H,m); 2.70-2.90(2H, m); 4.90-5.10(1H, m);7.00-7.40(3H,m); 7.40-7.80(6H, m);7.80-8.25(4H, m);13.16(1H,exchangeable, broad s)MS AP−(M−1)=499 21 o-cyanophenyl2-methylphenyl S 0 MS AP−(M−1)=326 22 4-fluorophenyl 3,4-dichlorophenylS 0 MS AP−(M−1)=373 23 4-fluorophenyl 4-fluorophenyl S 0 MS AP−(M−1)=32324 4-fluorophenyl

S 0 MS AP−(M−1)=362 25 o-cyanophenyl phenyl S 0 MS AP−(M−1)=312 26o-cyanophenyl 3,4-dichlorophenyl S 0 MS AP−(M2)=380 27 o-cyanophenyl4-fluorophenyl S 0 MS AP−(M−1)=330 28 o-cyanophenyl

S 0 MS AP−(M−1)=369 29 4-bromophenyl phenyl S 0 DMSO-d6: 2.00-2.20(2H,m); 3.00-3.25(2H, m); 4.58 (1H, m); 6.80-6.90(2H, m); 7.15-7.30(2H, m);7.30-7.65 (6H, m); 13.28(1H, exchangeable, broad s) 30 4-bromophenyl3,4-dichlorophenyl S 0 DMSO-d6: 2.05-2.25(2H, m); 3.10-3.25(2H, m);4.83(1H, m); 6.80-6.90 (2H, m); 7.15-7.30(1H, m); 7.30-7.50(2H, m);7.50-7.70(2H, m); (N.B.: acid OH not observed) 31 o-phenylbenzyl3,4-dichlorophenyl S 0 DMSO-d6: 1.80-2.00(2H, m); 2.90-3.15(2H, m);3.90-4.00(1H, m); 4.25- 4.70(2H, m); 7.20-7.30 (2H, m); 7.30-7.50(7H,m); 7.50-7.60(3H, m); 12.84(1H, exchangeable, broad s) 324-{3,4-dichloro- 2-methylphenyl S 0 CDCl₃: 2.15-2.50(3H, s+phenyl}phenyl 2H, m); 3.00-3.30(2H, m); 4.94(1H, m); 6.90- 7.05(2H, m);7.05-7.20 (3H, m); 7.20-7.40(2H, m); 7.40-7.70(4H, m) (N.B.: acid OH notobserved) MS AP−(M−2)=445 33 4-trifluoromethyl-phenyl 3-methylphenyl S 0MS ES−(M−1)=369 34 4-trifluoromethyl-phenyl 4-methylphenyl S 0 MSES−(M−1)=369 35 4-trifluoromethyl-phenyl 2,6-dimethylphenyl S 0 MSES−(M−1)=383 36 4-trifluoromethyl-phenyl 2-naphthyl S 0 MS ES−(M−1)=40537 4-trifluoromethyl-phenyl 1-naphthyl S 0 MS ES−(M−1)=405 384-trifluoromethyl-phenyl 2-tert-butylphenyl S 0 MS ES−(M−1)=397 394-trifluoromethyl-phenyl 2-methoxyphenyl S 0 MS ES−(M−1)=385 404-trifluoromethyl-phenyl 4-methoxyphenyl S 0 MS ES−(M−1)=385 414-trifluoromethyl-phenyl 2,4-dimethyl-phenyl S 0 CDCl₃: 2.10-2.45(3H, s+3H, s+2H, m); 2.90-3.20 (2H, m) 4.93(1H, m); 6.80-7.05(4H, m) 7.15-7.30(1H, m); 7.45-7.60 (2H, m); (N.B.: acid OH not observed). 424-trifluoromethyl-phenyl 2,5-dimethyl-phenyl S 0 CDCl₃: 2.15-2.50(3H, s+3H, s+2H, m); 2.95-3.20 (2H, m); 4.95(1H, m) 6.85-7.15(5H, m); 7.45-7.60(2H, m); (N.B.: acid OH not observed). 43 4-trifluoromethyl-phenyl3,4-dichloro-phenyl S 0 MS ES−(M−2)=423 44 4-trifluoromethyl-phenyl4-chlorophenyl S 0 MS ES−(M−1)=389 45 4-trifluoromethyl-phenyl3-chlorophenyl S 0 MS ES−(M−1)=389 46 4-trifluoromethyl-phenyl2-chlorophenyl S 0 MS ES−(M−1)=389 47 4-trifluoromethyl-phenyl

S 0 MS ES−(M−1)=360 48 4-trifluoromethyl-phenyl

S 0 MS ES+(M+1)=408 49 4-methoxyphenyl 3-methylphenyl S 0 MSES−(M−1)=331 50 4-methoxyphenyl

S 0 MS ES−(M−1)=322 51

2-methylphenyl S 0 CDCl₃: 2.20-2.45(1H, m+3H, s); 2.45-2.85(2H,m);2.85-3.05(1H, m);5.25(1H, m); 6.71(1H,m); 7.00-7.30(4H, m);7.50-7.85(2H,m); (acidOH not observed).MS ES−(M−1)=370 52

4-methoxyphenyl S 0 MS ES−(M−1)=386 53

4-chlorophenyl S 0 MS ES−(M−1)=390 54

phenyl S 0 MS ES−(M−1)=356 55

2-ethylphenyl S 0 MS ES−(M−1)=384 56

2,4-dimethyl-phenyl S 0 CDCl₃: 2.20-2.45(3H, s+3H, s+1H, m);2.45-2.75(2H, m); 2.90-3.00(1H,m); 5.22(1H, m); 6.65-7.20(4H, m);7.50-7.80(2H, m); (N.B.: acid OH not observed).MS ES−(M−1)=384 574-trifluoromethyl-phenyl CH₃ S 0 CDCl₃: 2.12(3H, s); 2.25- 2.45(2H, m);2.60-2.90 (2H, m); 5.00(1H, m); 6.84(2H, d, J=8.79 Hz); 7.57(2H, d,J=8.79 Hz); (N.B.: acid OH not observed) 58 4-trifluoromethyl-phenylphenyl S 2 CDCl₃: 2.20-2.80(2H, m); 3.10-3.55(2H, m) 4.91(1H, m);6.75-7.05 (2H, m); 7.40-7.80(5H, m); 7.80-8.10(2H, m); (N.B.: acid OHnot observed). MS ES−(M−1)=387 59 4-trifluoromethyl-phenyl 2-ethylphenylS 0 CDCl₃: 1.10-1.30(3H, t, J= 7.49 Hz); 2.20-2.40 (2H, m);2.70-2.80(2H, q, J=7.49 Hz); 3.00-3.30 (2H, m); 4.94(1H, m);6.85-7.00(2H, m); 7.05- 7.45(4H, m); 7.45-7.65 (2H, m); (N.B.: acid OHnot observed). 60 4-trifluoromethyl-phenyl

S 0 CDCl₃: 2.20-2.40(2H,m); 3.20-3.40(2H, m);4.88(1H, m); 6.70-6.90(2H,m); 7.35-7.50(2H,m); 7.80-8.50(4H, m);8.85-9.00(2H, m); 9.25-9.40(1H,m)(N.B.: acidOH not observed)

Analogously, the following compounds have been synthesized:

EXAMPLE 61

MS ES+(M+1)=380, 382.

EXAMPLE 62

MS ES−(M−1)=363, 365.

EXAMPLE 63

MS ES−(M−1)=331.

EXAMPLE 64

MS ES−(M−1)=385.

EXAMPLE 65

MS ES−(M−1)=365, 367.

EXAMPLE 66

MS ES−(M−1)=391.

EXAMPLE 67

MS ES−(M−1)=329.

EXAMPLE 68

MS ES−(M−1)=377, 379.

EXAMPLE 69

MS ES+(M+1)=407, 423.

EXAMPLE 70

MS ES−(M−1)=369.

EXAMPLE 71

(DMSO-d6): 1.94-2.11 (2H, m); 2.80-3.03 (2H, m); 4.71-4.92 (1H, m);6.55-6.83 (2H, m); 6.90-7.70 (2H, m); 7.12-7.33 (2H, m); 7.45-7.73 (2H,m).

NB: exchangeable protons not observed.

EXAMPLE 72

(CDCl3):1.79-2.11 (2H, m); 2.17 (3H, s); 2.59-2.93 (2H, m); 4.60-4.77(1H, m); 4.92 (2H, s); 6.43-6.57 (2H, m); 6.62-6.76 (2H, m); 6.99-7.13(3H, m); 7.19-7.35 (4H, m); 7.70-7.89 (2H, m).

NB: acid H not observed

EXAMPLE 73

m.p. 94°C.;

(CDCl3): 1.12-1.29 (3H, m); 2.17-2.44 (8H, m); 2.60-2.81 (2H, m);2.98-3.27 (2H, m) 4.88-5.06 (1H, m); 6.60-7.28 (6H, m); 11.24 (1H, s).

EXAMPLE 74

m.p. 67° C.;

(CDCl3): 02-2.57 (5H, m); 2.94-3.32 (2H, m); 4.86-5.07 (1H, m);6.76-7.06 (3H, m); 7.06-7.30 (3H, m); 7.44-7.67 (2H, m); 9.68 (1H, broads).

EXAMPLE 75

(CDCl3): 2.11-2.44 (5H, m); 2.96-3.21 (2H, m); 3.74 (3H, s); 4.80-4.97(1H, m); 6.84-6.97 (2H, m); 7.03-7.33 (4H, m); 7.47-7.58 (2H, m).

EXAMPLE 76

m.p. >250°C.;

(DMSO-d6): 1.95-2.18 (2H, m); 2.25 (3H, s); 2.98-3.18 (2H, m); 4.27-4.50(1H, m); 6.83-7.22 (5H, m); 7.22-7.37 (1H, m); 7.41-7.64 (2H, m).

EXAMPLE 77

(DMSO-d6): 1.98-2.32 (10H, m); 2.96-3.17 (4H, m); 4.43-4.62 (2H, m);6.88-7.21 (10H, m); 7.21-7.33 (2H, m); 7.44-7.58 (4H, m).

EXAMPLE 78

MS ES+(M+1)×417;

(CDCl3): 2.21-2.59 (2H, m); 2.67 (3H, s); 3.21-3.51 (2H, m); 3.74 (3H,s); 4.73-4.95 (1H, m); 6.72-6.95 (2H, m); 7.26-7.62 (5H, m); 7.79-8.09(1H, m).

EXAMPLE 79

MS ES−(M−1)×401;

(CDCl3): 2.29-2.70 (5H, m); 3.22-3.54 (2H, m); 4.76-5.01 (1H, m); 6.54(1H, broad s); 6.78-6.97 (2H, m); 7.19-7.43 (2H, m); 7.43-7.63 (3H, m);7.87-8.08 (1H, m).

EXAMPLE 80

MS ES+(M+1)=401;

(CDCl3): 1.93-2.70 (5H, m); 2.70-3.22 (2H, m); 3.73 and 3.75 (3H, 2s);4.65-4.99 (1H, m); 6.72-7.04 (2H, m); 7.07-7.63 (5H, m); 7.75-8.00 (1H,m).

EXAMPLE 81

MS ES−(M−1)=385;

(CDCl3): 2.06-2.69 (5H, m); 2.87-3.32 (2H, m); 4.67-5.15 (1H, m); 5.80(1H, broad s); 6.81-7.04 (2H, m); 7.14-7.33 (1H, m); 7.33-7.60 (4H, m);7.79-7.99 (1H, m).

1. Compound of the formula I:

in which: A represents carboxyl; (C₆-C₁₈)aryloxycarbonyl in which thearyl group is optionally substituted; (C₁-C₁₄)alkoxycarbonyl in whichthe alkyl group is optionally substituted; —CO—NHOH; -tetrazolyl; Brepresents an optionally substituted ethylene group —CH₂—CH₂—; R¹represents a hydrogen atom; optionally substituted (C₁-C₁₄)alkyl;optionally substituted (C₆-C₁₈)aryl; optionally substituted heteroaryl;(C₆-C₁₈)aryl(C₁-C₁₄)alkyl in which each of the aryl and/or alkylradicals are optionally substituted; and heteroaryl(C₁-C₁₄)alkyl inwhich each of the heteroaryl and/or alkyl radicals are optionallysubstituted; Z represents S or Se; n is an integer equal to 0, 1 or 2;R² represents optionally substituted (C₆-C₁₈)aryl; optionallysubstituted heteroaryl; or optionally substituted heterocycle containingan aromatic moiety; and when R¹ represents optionally substituted(C₆-C₁₈)aryl, then R² can also represent (C₁-C₁₄)alkyl; it beingunderstood that when R¹ represents naphthyl or 4-methoxyphenyl, Arepresents carboxyl or methoxycarbonyl, B represents ethylene, nrepresents 0, and P represents S or Se, then R² does not representphenyl, the stereoisomers thereof and the addition salts thereof withacids or bases.
 2. Compound of the formula I according to claim 1, inwhich A represents —COOH.
 3. Compound of the formula I according toclaim 1, in which B represents ethylene.
 4. Compound of the formula Iaccording to claim 1, in which R¹ represents benzyl optionallysubstituted on the phenyl nucleus; optionally substituted phenyl; oroptionally substituted pyridyl; the substituents on the phenyl nucleiand on the pyridyl nucleus preferably being chosen from halogen atomsand cyano groups, trifluoromethyl groups, (C₁-C₆)alkyl groups or(C₁-C₆)alkoxy groups or a (C₆-C₁₈)aryl group itself optionallysubstituted by halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CF₃ or CN. 5.Compound of the formula I according to claim 1, in which R² representsoptionally substituted phenyl; optionally substituted benzopyridine;optionally substituted benzothiazole; optionally substituted quinolyl;optionally substituted naphthyl; optionally substituted triazole; or

which is optionally substituted, the substituents being halogen atoms,—CN, —CF₃, (C₁-C₆)alkyl or (C₁-C₆)alkoxy groups or a (C₆-C₁₈)aryl groupoptionally substituted by halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, CF₃ or—CN.
 6. Compound of the formula I according to claim 1, wherein Zrepresents S.
 7. Process for preparing a compound of the formula Iaccording to claim 1, in which A represents —COOH, Z represents S andn=0, comprising reacting a compound of formula II:

in which B and R¹ are as defined in claim 1, with a thiol of formulaIII:R²—SH  III in which R² is as defined in claim 1, in the presence of abase.
 8. Process according to claim 7, for the preparation of anenantiomer of the formula Ib

in which: A, B, Z, R¹, n and R² are as defined in above and * denotes anasymmetric carbon, wherein the compound of the formula II is theenantiomer of the formula:

in which B and R¹ are as defined for formula Ib and * denotes anasymmetric carbon of the same configuration as the equivalent carbon ofthe formula Ib.
 9. Process for preparing a compound of the formula Iaccording to claim 1, in which A represents —COOH, Z represents Se andn=0, comprising reacting a selenium compound of formula IV:R²—Se—Se—R²  IV in which R² is as defined in claim 1, with an organic ormineral base, and the resulting compound is then reacted with a compoundof the formula II:

in which B and R¹ are as defined in claim 1 for formula I.
 10. Processfor preparing a compound of the formula I according to claim 1, in whichA represents —COOH and n≠0, comprising reacting a compound of theformula I in which n=0:

in which R¹, B, Z and R² are as defined in claim 1 and A represents—COOH, with an oxidizing agent.
 11. Pharmaceutical compositioncomprising an effective amount of at least one compound chosen from acompound of the formula I according to claim 1 and the compounds of theformula I for which R¹ represents naphthyl or 4-methoxyphenyl; Arepresents carboxyl or methoxycarbonyl; B represents ethylene; nrepresents 0; Z represents S or Se and R² represents phenyl, incombination with at least one pharmaceutically acceptable vehicle.
 12. Aprocess according to claim 10, wherein the oxidizing ism-chloroperbensoic acid.
 13. A pharmaceutical composition comprising aneffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 14. A method for treating diabetes, hyperlididemiaor atherosclerosis due to hyperlipidemia, comprising administering to ahost in need thereof an effective amount of a compound of claim 1.